Method for preparing 7-substituted cephalosporins by replacement of oxygen containing groups

ABSTRACT

Disclosed is a method for replacing 7-lower alkanoyloxy and 7aroyloxy groups from cephalosporins with other lower alkanoyloxy, lower alkoxy, aryloxy, amino, lower alkyl amino and azido moieties.

United States Patent Dolfini et al. 1 Oct. 7, 1975 1 METHOD FOR PREPARING {51] Int. Cl. .4 C071) 501/02 7-SUBSTITUTED CEPHALOSPORINS BY [58] Field of Search 260/243 C REPLACEMENT OF OXYGEN CONTAINING GROUPS [56] References Cited [75] Inventors: Joseph Edward Dolfini, Princeton; UNITED STATES PATENTS w n A. slusarchyk ll Mead; 3,733,320 5/1973 Pines El 211 3, 260/243 C 3,775,410 11/1973 Christensen e131. 260/243 C Henry Koster Pennmgton 3,780,037 12/1973 Hazen 0 260/243 c all of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc., Primary Examiner-Nicholas S. Rizzo Princeton, NJ. Attorney, Agent, or Firm-Lawrence S. Levinson; Filed: Sept. [973 Merle J, Smith; Stephen B, DHVIS [21] Appl. No.1 394,944 [57] ABSTRACT Related Application Data Disclosed is a method for replacing 7-1ower al- [63] cominualiomimpan of Ser- No. 3l247l Dec- 6 kanoyloxy and 7aroyloxy groups from cephalosporlns 1972, abandoned.

US. Cl 260/243 C; 424/246; 260/239.1

with other lower alkanoyloxy, lower alkoxy, aryloxy, amino, lower alkyl amino and azido moieties.

8 Claims, No Drawings METHOD FOR PREPARING 7-SUBSTITUTED CEPHADOSPORINS BY REPLACEMENT OF OXYGEN CONTAINING GROUPS This application is a continuation-in-part of our copending application, Ser. No. 312,47], filed Dec. 6, 1972, now abandoned.

Cephalosporins are of considerable interest to the pharmaceutical industry. Presently compounds of this type are being employed as potent antimicrobials. As in the case of the penicillins and tetracyclines, researchers are now trying to improve on the activity of these antibiotics by modifying the naturally occurring cephalosporins. Unfortunately, most antibiotics are quite complex and therefore simple reactions cannot be utilized to introduce the desired modifications. Usually considerable effort must be extended to devise a method for modifying such complex entities. Herein is described such a procedure which gives rise to useful antibacterial cephalosporins.

This invention relates to a method for the conversion of cephalosporins of the formula:

CO R

CO R 3 wherein R, is phthalimido acylamino, a Schiff base such as benzalimino, or a substituted Schiff base; R is lower alkanoyloxy or aroyloxy or substituted aroyloxy; R is hydrogen, a cation such as Nafl Li*, Ca, k*, NH} and (C H NH* or a readily clevable ester such as t-butyl, trichloroethyl, trimethylsilyl or pmethoxybenzyl; R is methyl, acetoxymethyl or carbamoyloxymethyl; and R is lower alkoxy, other lower alkanoyloxy, aryloxy, azido, amino, mono-and di-lower alkyl amino, by the use of certain mercury, silver and thallium salts and an appropriate source of R such as a lower alkyl alcohol, a phenol or its salt, amines, lower alkyl amines, di-lower alkyl amines, lower alkanoic acid or salt thereof, or metal azides Acyl is defined in this invention as:

wherein R, R and R are hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, lower alkoxy lower alkyl, thienyl, substituted thienyl, phenyl, substituted phenyl, phenoxy, substituted phenoxy, amino, nitro, halo, mercapto, lower alkylmercapto, lower alkylmercapto lower alkyl, phenylthio and substituted phenylthio wherein the substituents on the thienyl, phenyl, phenoxy, and phenylthio may be one or more of the following: lower alkyl, lower alkoxy, halo, nitro, amino and trifluoromethyl and n is either 0 or an integer from I to 4.

b. RCO wherein R is hydrogen, amino, phenyl, substituted phenyl, lower alkoxy, thienyl, substituted thienyl, phenoxy, lower alkylthio, substituted phenoxy, B-lower alkenyl, B-lower alkylthior lower alkenyl, B-lower alkoxy lower alkenyl and B-lo. wer alkenyloxy lower alkyl, wherein the substituents on the thienyl, phenyl and phenoxy may be one or more of the following: lower alkyl, lower alkoxy, halo, nitro, amino and trifluoromethyl.

Lower alkyl is defined as a branched or straight chain having from one to six carbon atoms. This definition also applies to terms incorporating lower alkyl with other groups, such as aryl lower alkyl which is intended to mean an aryl group linked to an alkyl group having one to six carbon atoms.

Aryl is defined as phenyl and a and B-naphthyl.

Substsituted as in substituted Schiff base, substituted aryl or substituted benzalimino is intended to mean unless specifically defined otherwise as monoor disubstituted wherein said substituents may be lower alkyl, lower alkoxy, nitro, chloro, fluoro or trifluoromethyl.

Numerous modifications of the naturally occurring cephalosporins have already been made in an effort to enhance antimicrobial activity with a certain degree of success being achieved. One of the positions of the cephalosporin nucleus which a number of researchers have focused upon as a place for introducing new groupings is the 7-position. Since substituents on the 7a-position tend to demonstrate higher degrees of antimicrobial activity than 7B-substituents, attempts to devise new syntheses for introducing substituents into this position are generally directed to the introduction of 7a-substituents.

This invention teaches how one may convert the readily prepared 7-acyloxy derivatives to compounds wherein the 7-acyloxy group is replaced by lower alkoxy, aryloxy, other lower alkanoyloxy, axido, amino and lower alkylamino groups.

The above described starting materials of the structure cooR wherein R, to R are as previously described, by the use of a reagent to supply the grouping which shall ultimately be R in the presence of a mercury, silver or thallium salt catalyst. The cations to be used as catalysts are preferably in their highest oxidation sate (ic form) and the anions are preferably one of the following: lower alkoxy, lower alkanoyloxy, cyano, nitrate, fluoro, bromo, chloro and sulfate.

For R to be lower alkoxy, the reagent may be the corresponding lower alkanol. In turn, lower alkanoyloxy is introduced by utilizing the corresponding lower alkanoic acid or a heavy metal salt thereof, (mercury, silver, etc.); aryloxy is introduced byutilizing a substituted phenol or salt thereof, azido is introduced by the use of an azide salt, such as potassium or sodium azide in the presence of catalyst; amino is introduced by the use of an excess of amine in the presence of catalyst.

The reactions of this invention are preferably conducted in inert solvents, such as dimethoxyethane, dioxane, dimethylformamide and tetramethylurea at temperatures from about 10 to about I 10C, preferably from about to about 70C. However, where a lower alkoxy group is being introduced, the correspnding alcohol may be employed as the reaction solvent. The replacement reactions of this invention take place at a relatively rapid rate so that the reaction time required is usually from about a few minutes to several hours at ambient temperature.

While this reaction is of a general nature, the preferred compounds to be prepared by the process of this invention are those of the formula:

wherein R, is benzalimino, p-nitrobenzalimino, pmethoxybenzalimino, thienylacetamido, a-aminowhich may also be encountered at other sites in compounds of this invention.

The cephalosporins which may be prepared by this invention are useful against gram-positive bacteria, such as Staphylococcus aureus and Streptococcus pyrogenes, and especially against gram-negative bacteria such as Escherichia coli and Proteus vulgarz's.

EXAMPLE 1 7oz-Methylthio-7-benzaliminodesacetoxycephalosporanic Acid t-Butyl Ester (from Methylthiolation of Schiff Base) Method A. Methyl Methanethiosulfonate Procedure To a stirred solution of 7-benzaliminodesacetoxy cephalosporanic acid t-butyl ester (13.5 g, 37.7 mmol) in 200 ml dimethoxyethane at 20 under N potassium t-butoxide (4.22 g, 37.7 mmol) is added. A deep red solution is formed which is stirred for 1.5 minutes and methyl methanethiolsulfonate (4.75 g, 37.7 mmol) is added. When the color of the solution turns from deep red to yellow, the reaction mixture is poured into pH 6.5 buffer (300 ml). The mixture is extracted with CHCl and the CHCl extract is washed with saturated NaCl solution, dried (Na SO and evaporated to a residue. Recrystallization of the residue from acetonehexane gives 5.38 g (35% yield) 7a-methylthio Schiff base, ir (CHCI 1764 (B-lactam C=O), 1715 (conjugated ester C=O), 1628 (C=N), and 1130 cm (SCH pmr (DCC1 78.45 (9 H,s,t-butyl), 7.93 (3H,s,C4I-CH,,), 7.70 (C-6), 2.02.8 (5H,m,aromatics), 1.91 lH,s,CH=N); mass spectrum, molecular ion at l (calcd. for C34] HzqNgO gSz l An analytical sample that is recrystallized from CH Cl -pet ether melts at about Method B. Methysulfenyl Chloride Procedure The procedure in part A is followed using methylsulfenyl chloride in place of methylmethanethiolsulfonate. From (20.3 g, 56.5 mmol) Schilf base, (6.33 g, 56.5 mmol) potassium t-butoxide, (4.6 g, 56.5 mmol) methylsulfenyl chloride, and 250 m1 dimethoxyethane is obtained 7.70 g (34% yield) crystalline Schiff base.

EXAMPLE 2 7a-Methylthio-7-benzaliminocephalosporanic Acid t-Butyl Ester By following the procedure in Example I, but substituting 7-benzaliminocephalosporanic acid t-butyl ester for the Schiff base substrate, the desired product is obtained as a crystalline product having m.p. l24125C.

EXAMPLE 3 7oz-Phenylthio-7-(p-nitrobenzalimino )cephalosporanic Acid p-Methoxybenzyl Ester By following the procedure in Example 1, method B, but substituting 7(p-nitrobenzalimino)cephalosporanic acid p-methoxybenzyl ester for the Schiff base substrate and phenylsulfenyl chloride for methylsulfenyl chloride, the desired product is obtained as an amorphous product.

EXAMPLE 4 7a-Ethylthio-7-( pmethoxybenzalimino)desacetoxycephalosporanic Acid t-Butyl Ester By following the procedure in Example 1, method B, but substituting 7-(pmethoxybenzalimino)desacetoxycephalosporanic acid t-butyl ester for the Schiff base substrate and ethylsulfenyl chloride for methylsulfenyl chloride. the desired product is obtained as an amorphous material.

EXAMPLE 5 7a-Methylthio-7-phenylacetamidodesacetoxycephalosporanic Acid t-Butyl Ester To a stirred solution of 7a-methylthio Schiff base from Example 1 (2.54 g, 6.28 mmol) in 30 ml of CH Cl at room temperature under N phenylacetyl chloride (0.84 ml. 6.28 mmol) and water (0.15 ml, 8.34 mmol) are added. The mixture is stirred for 18 hours, diluted with CH Cl and poured into water. The pH is adjusted to 7.5, and the CH Cl layer is washed successively with water, dilute aqueous NaHSO and water. The CH Cl solution is dried (Na SO and evaporated in vacuo to a residue that crystallized from Et- OCH CI to give 1.18 g (43% yield) of the above named product: ir (CHCl 1775 (,B-lactam C=O), 1712 (conjugated C=O), 1675 (amide C=O), 1480 (amide ll band), and H30 cm (S-CH pmr (DCCl 18.50 (9H,s,t-butyl), 7.92 (3H,s,C=CCH 7.75 (3H,s,SCH,-,), 6.82 (2H,broad singlet, C-2),

1? 6.36 2H,broad singlet,Ar-CH C 5.09 (lH,s,NH). An analytical sample is recrystallized from Et OCHCl (mp l74l75).

EXAMPLE 6 7a-Methylthio-7-phenylacetamidocephalosporanic Acid t-Butyl Ester By following the procedure in EXample 5, but substituting 7a-methylthio-7-benzaliminocephalosporanic acid t-butyl ester for the Schiff base substrate, the desired product is obtained as an amorphous solid: pmr (DCCl 17.92 (3H,s,O-acetyl), 7.77 (3H,s,SCh 6.60 (2H,broad singlet,C-2), 6.24 (2H,s,ArCH and 5.07 (lH,s,C-6).

EXAMPLE 7 7oz-Acetoxy-7-phenylacetamidodesacetoxycephalosporanic Acid t-Butyl Ester a. To a suspension of the 7a-methylthio amide (Example 5) (651 mg, 1.5 mmol) in a 5 ml of dimethoxyethane is added mercuric acetate (478.5 mg, 1.5 mmol). The mixture is stirred under nitrogen for minutes at room temperature. The precipitate is filtered and washed with dimethoxyethane yielding 413 mg pale yellow powder. The filtrate is evaporated to a residue that is taken up in benzene-water. The benzene layer is washed with water, dried (Na SO and evaporated to give 620 mg (93% yield) of the above named 7a-acetoxy t-butyl ester as an almost colorless oil: ir (CHCl 1785 (B-lactam C=O), 1750(sh) (ester C=O), 1720-1685 (broad band, conjugated C=O and amido C=O), and 148Ocm (amide llband); pmr (DCCLJ 18.48 (9H,s,t-butyl), 7.90

4.87 (lH,s,C-6), 2.85 (lH,s,N-H), 2.67 (5H,s,aromatics); mass spectrum, no molecular ion but m/e 344 (MCH,-,COOH).

b. To 109 mg (0.25 mmole) of methylthio amide (Example 5) in 2 ml of acetic acid is added 164 mg (2 mmoles) of sodium acetate followed by mg (0.25 mmole) of mercuric acetate. The mixture is stirred for 15 minutes at room temperature, and the acetic acid is removed in vacuo. The residue is taken up in benzene and water. The benzene layer is washed with aqueous sodium chloride solution, dried (Na SO and evaporated to give 1 12 mg of 7a-acetoxy-7- phenylacetamidodesacetoxycephalosporanic acid tbutyl ester as a residue.

EXAMPLE 8 7a-Acetoxyand B-acetoxy-phenylacetamidodesacetoxycephalosporanic Acid t-Butyl Esters A mixture of 63 mg (0.14 mmole) of 7a-acetoxy compound from Example 7 and 45 mg (0. 14 of mercuric acetic in 0.5 ml of dimethylformamide is stirred under nitrogen at room temperature for 25 minutes. The mixture is taken up in water and benzene, and the benzene layer is washed twice with water, dried (Na S0 and evaporated in vacuo to give 58 mg of yellow residue consisting of approximately equal quantities of 7a-acetoxy-7-phenylacetamidodesacetoxycephalosporanic acid t-butyl ester and 7B-acetoxy-7- phenylacetamidodesacetoxycepha]osporanic acid tbutyl ester: pmr (DCCl 7a-acetoxy epimer,

6.98 (2H,broad singlet, C-2), 6.32

4.87 (1H,s,C-7); 7B-acetoxy epimer, 17.87

6.77 (2H,broad singlet, C-2), 6.37

4.82 I H,s,C-7).

EXAMPLE 9 7-Benzalimino-7a-acetoxydesacetoxycephalosporanic Acid t-Butyl Ester A mixture of mercuric acetate (431 1 mg, 0. I35 mmol) and the methylthio Schifi base from Example 1 (500 mg, 0.124 mmol in dimethoxyethane (20 ml is stirred at room temperature for 30 minutes. Dilution with anhydrous ether ml) and filtration through Celite removes insoluble material. After stripping solvent under reduced pressure, the residue is taken up in ether and washed with 5% bicarbonate solution and water. The organic layer is treated with Norite, and the volume of solvent is reduced, yielding the above named product as an amorphous solid.

EXAMPLE l To 63 mg (0.14 mmole) of 7a-acetoxy compound (Example 7) in 0.4 ml of dimethylformamide is added 92 mg I.4 mmole) of sodium azide followed by 45 mg (0. l4 mmole) of mercuric acetate. The mixture is stirred under nitrogen for 30 minutes at room temperature. The solvent is removed under reduced pressure, and the residue is taken up in benzene and water. The benzene layer is washed three times with water, dried (Na SO and evaporated yielding 60 mg of residue consisting of 7a-azidoand 7B-azido-7- phenylacetamidodesacetoxycephalosporanic acid tbutyl esters: ir (CHCI 2070 and 2l30cm azide; I780 (B-lactam C=O), 1715 (ester C=O), l670cm (amide C=O).

EXAMPLE I l Methanol Solvolysis of 7a-Acetoxyand 'IB-acetoxy-7-phenylacetamidodesacetoxycephalosporanic Acid t-Butyl Esters To a solution of 465 mg 1.04 mmole) of an approximately 50:50 mixture of 7a-acetoxy and 7B-acetoxy epimers in 3 ml of methanol is added 332 mg (1.04 mmole) mercuric acetate. The mixture is stirred under nitrogen at room temperature for 40 minutes. The methanol is removed under reduced pressure, and the residue is taken up in benzene and water. The benzene layer is washed with water, dried (Na SO and evaporated to give 430 mg of residue consisting of 7amethoxyand 7B-methoxy-7- phenylacetamidodesacetoxycephalosporanic acid esters. The residue is subjected to slow fractional crystallization from small amounts of CH OH, which yields 400 mg pale yellow crystalline a-methoxy epimer a residue from crystal washings, and I20 mg mother liquor whose pmr spectrum indicates a 40:60 mixture of a a-methoxy and B-methoxy epimers, respectively. Slow crystallization of this mixture of epimers gives additional crystalline a-methoxy epimer and 60 mg of mother liquor whose pmr spectrum indicates a mixture of 70% B-methoxy epimer and 30% o-methoxy epimer.

The crystalline a-methoxy epimer, on recrystallization from CH Oh has: mp l75l76; ir spectrum (CHCI I770 (B-lactam C=O), l7l0 (conjugated C=O), I690 (amide C=O), II58. I134, 1106, and I086 cm (COC and CSC); pmr (DCCI 60 MHz), 78.50 9H,s,t-butyl), 7.90 (3H,s,C=C-CH;,), 6.55 (3H,s,OCH;,), 6.75, 6.95 2H,q,J=l7Hz, C-2),

4.98 (lH,s,C-6), 3.32 (lH,b,Nl-l), 2.67 (H,s,aromatics); mass spectrum molecular ion at rn/e 4l8. I584 (calcd. for C H N O S: 4l8.l560).

The mother liquor containing 70% B-methoxy epimer shows: ir (CHCl I770 (B-lactam C=O), l7l0 (conjugated C=O), I690 (amide C=O), and 1155, 1138, 1100 and l090cm; prnr (DCCI 78.50 (9H,s,t-

4.83 (IH,s,C-6), 2.67 (5H,s,aromatics).

EXAMPLE 12 7-Benzalimino-7oz-methoxydesacetoxycephalosporanic Acid t-Butyl Ester A mixture of mercuric acetate (I mmol) and the 7- acetoxy Schitf base I mmol) from Example 9 in methanol is stirred for 30 minutes at room temperture. The mixture is evaporated to a residue which is taken up in benzene and water. The benzene layer is washed with water, dried (Na SO and evaporated to a residue. Crystallization of the residue from methanol gives the desired product having mp l4l142; ir (CHCI I770 (B-lactam C O), l7l5 (t-butyl ester C=O), l635cm' (C=N); pmr (DCCI 78.47 (9H,s,t-butyl CH 7.78 (3H,s,CH 6.98 IH,d,J ,.=I7Hz,C-2), 6.55 (lH,d.-l =l7HZ,C-2), 6.39 (3H,s,OCH 4.92 lH,s,C-6), 1.97-2.75 (5H,complex m, aromatic), 1.30 IH,s,azomethine CH).

EXAMPLE l3 7 -Benzalimino-7a-ethoxydesacetoxycephalosporanic Acid t-Butyl Ester The procedure described in Example 12 is used to prepare the above named compound. The acetoxy Schiff base from Example 9 is solvolyzed in abolsute ethanol and catalyzed by the addition of b 1 equivalent of mercuric acetate. After the workup, the 7a-ethoxy Schiff base is obtained; pmr (DCCI 78.70 (3H,t,OCH CH 8.42 (9H,s,t-butyl CH 7.93 (3H,s,CH 6.73 (2H,dd,C-2), 6. I0 (2H,q,OCH CH 4.92 (lH,s,C-6), 1.95-2.67 (5H,complex m, aromatic; M, m/e 402 (C ,H .,N O,S 402).

EXAMPLE 14 Sodium Salts of 7a-Methoxy-7-propionamidodesacetoxycephalosporanic Acid and 7B-Methoxy-7-propionamidodesacetoxycephalosporanic Acid The procedure described in Example II is used to solvolyze the sodium salt of 7a-acetoxy-7- propionamidodesacetoxycephalosporanic acid. However, the workup is modified such that the residue from the reaction mixture is taken up in water and, after adjusting the acidity of the aqueous solution to pH 3.5, the aqueous solution is exhaustively extracted with methylene chloride. The combined extracts are dried (Na SO and solvent is removed under reduced pressure. The residue is suspended in methanol and one equivalent of sodium methoxide is added while stirring vigorously. Removal of solvent in vacuo yields a mixture of the desired sodium salts as an amorphous solid.

General Procedures for the metal catalyzed solvolysis of the 7-alkanoyloxy or 7-aroyloxy cephems (1) shown in Table I.

To a solution or suspension of the 7-alkanoyloxy or 7-aroyloxy cephem in the indicated anhydrous solvent system, is added 1.0 equivalent of metal catalyst and 4-10 equivalents of organic salt, if indicated in table. The heterogeneous mixture is stirred, preferably under an inert atmosphere, at the temperature shown in Table l. The reaction is best followed to completion by monitoring the mixture on thin layer chromatography since reaction times are found to vary. After removal of the solvent system in vacuo, the residue is diluted with an organic solvent, which is immiscible with water, and filtered to remove insoluble materials. The solution is washed with dilute aqueous sodium bicarbonate solution and water, the organic layer is dried, and solvent is removed under reduced pressure. An amorphous residue is obtained containing the appropriate cephem derivative indicated in Table I.

TABLE l Continued R. R2 R3. R, R Catalyst Solvent Temp.

NaN O2N-CH=N- ()Acla) t hut \l CHgOac -N (rx+[3] Hg(OAc) DMF 25 6 CH=N QALI r1] l-butyl CH (CHR)2N- Hg( OAc (CH hNH 25 (n+3) DMF What is claimed is: R 1. A process for the preparation of compounds of the R formula: 1 R

5 coon COOR wherein R, is selected from the group consisting of phthalimido, benzalimino, substituted benzalimino,

wherein R, is selected from the group consisting of phenyl, substituted phenyl. 1,4-cyclohexadienyl, phenoxy, substituted phenoxy thienylfuryl, phenylthio and substituted phenylthio,

wherein R is selected from the group consisting of wherein R is selected from the group consisting of lower alkyl, phenyl and substituted phenyl, and wherein said benzalimino, phenyl, phenoxy, or phenylthio substituent is one or two members selected from the group consisting of lower alkyl, lower alkoxy, nitro, chloro, fluoro and trifluoromethyl; R is selected from the group consisting of hydrogen, t-butyl, trichloroethyl, trimethylsilyl, p-methoxybenzyl, and a cation; R is selected from the group consisting of methyl, acetoxymethyl, and carbamoyloxymethyl; and R is selected from the group consisting of lower alkoxy, phenoxy, lower alkanoyloxy, amino, lower alkylamino, lower dialkylamino, and azido; which comprises reacting a compound of the formula wherein R is selected from the group consisting of lower alkanoyloxy and benzoyloxy; with a compound selected from the group consisting of a lower alkyl alcohol, phenol, lower alkanoic acid or its mercury or silver salt, sodium azide, potassium azide, ammonia, lower alkylamine, and lower dialkylamine at a temperature of from about lOC to about 1 10C in the presence of an effective catalytic amount of a catalyst selected from the group consisting of mercuric acetate, mercuric chloride, dimethoxy mercury, thallium acetate, silver tetrafluoroborate, silver acetate, and lead acetate.

2. The process of claim 1 wherein R is selected from the group consisting of benzalimino, pnitrobenzalimino, p-methoxybenzalimino, thienylacetamido, a-aminophenylacetamido, a-aminol,4-cyclohexadienylacetamido, phenylacetamido, and phenoxyacetamido; and R is selected from the group consisting of lower alkoxy, lower alkanoyloxy, phenoxy, and azido.

3. The process of claim 2 wherein R is acetoxy and R is selected from the group consisting of methoxy, ethoxy, propionyloxy, phenoxy, and azido.

4. The process of claim 3 wherein said catalyst is selected from the group consisting of mercuric acetate, dimethoxy mercury and silver tetrafluoroborate.

5. The process of claim 4 wherein R is phenylacetamido; R is methyl; R is t-butyl; R is azido; R is acetoxy; the reactant is sodium azide; and the catalyst is mercuric acetate.

6. The process of claim 4 wherein R is phenylacetamido; R is methyl; R is t-butyl; R is methoxy; R is acetoxy; the reactant is methanol; and the catalyst is mercuric acetate.

7. The process of claim 4 wherein R, is benzalimino; R is methyl; R is t-butyl; R is methoxy; R is acetoxy; the reactant is methanol; and the catalyst is mercuric acetate.

8. The process of claim 4 wherein R is benzalimino; R is methyl; R is t-butyl; R is ethoxy; R is acetoxy, the reactant is ethanol; and the catalyst is mercuric acelZlllC.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3 ,910,902 Page 1 of 2 DATED 1 Oct. 7, 1975 IN I Dolfini et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown betow:

Col. l, the first structure should be labeled I.

Col. 1, the second structure should be labeled II.

Col. 1 line 47 "phthalimido acylamino," should read phthalimido, acylamino,

Col. 1, line 50, "k should read --1 Col. 1, line 51, "clevable" should read -cleavable-.

Col. 2, line 50, "axido" should read azido-.

Col. 3, line 22, "byutilizing" should read by utilizing--.

Col. 4, line 5, "pyro" should read pyo- Col. 4, line 36, "Methysulfenyl" should read Methylsulfenyln Col. 5, line 40, "Ch should read -CH Col. 6, line 15, "B" should read -7B.

Col. 6, line 59, "431 1 mg. should read 431 mg..

Col. 7 line 47, "o-methoxy" should read -or-methoxy.

Col. 7, line 49, "CH Oh" should read -CH OH--.

Signed and Scaled this sixth Day of April1976 [SEAL] Arrest:

RUTH C. MASON C. MARS Ancsling Offi r HALL DANN ummissinner nj'larenrs and Trademarks UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION Page 2 of 2 PATENT NO. 1 3 1 ,902 DATED 1 10/7/75 INVENTOR(S) I Dolfini et al lt iscertihed that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Page 2 of Table 1, 2nd line under "R the structure should read 3 CH O@CH Page 2 of Table I, 7th line under "R the structure should read (or+B) Page 2 of Table I, 13th line under "R the structure should read 1 O2N@CH=N Col. 13, line 35, "phenoxy thienyl," should read phenoxy, thienyl,.

Signed and Scaled this A nest.-

RUTH C. MASON C. M Aum'mg fficer ARSHALL DANN Commissioner uflarenrs and Trademarks 

1. A PROCESS FOR THE PREPARING OF COMPOUNDS OF THE FORMULA:
 2. The process of claim 1 wherein R1 is selected from the group consisting of benzalimino, p-nitrobenzalimino, p-methoxybenzalimino, thienylacetamido, Alpha -aminophenylacetamido, Alpha -amino-1,4-cyclohexadienylacetamido, phenylacetamido, and phenoxyacetamido; and R5 is selected from the group consisting of lower alkoxy, lower alkanoyloxy, phenoxy, and azido.
 3. The process of claim 2 wherein R2 is acetoxy and R5 is selected from the group consisting of methoxy, ethoxy, propionyloxy, phenoxy, and azido.
 4. The process of claim 3 wherein said catalyst is selected from the group consisting of mercuric acetate, dimethoxy mercury and silver tetrafluoroborate.
 5. The process of claim 4 wherein R1 is phenylacetamido; R4 is methyl; R3 is t-butyl; R5 is azido; R2 is acetoxy; the reactant is sodium azide; and the catalyst is mercuric acetate.
 6. The process of claim 4 wherein R1 is phenylacetamido; R4 is methyl; R3 is t-butyl; R5 is methoxy; R2 is acetoxy; the reactant is methanol; and the catalyst is mercuric acetate.
 7. The process of claim 4 wherein R1 is benzalimino; R4 is methyl; R3 is t-butyl; R5 is methoxy; R2 is acetoxy; the reactant is methanol; and the catalyst is mercuric acetate.
 8. The process of claim 4 wherein R1 is benzalimino; R4 is methyl; R3 is t-butyl; R5 is ethoxy; R2 is acetoxy, the reactant is ethanol; and the catalyst is mercuric acetate. 